Kahalalide F and related compounds

• US 7,482,429 B2
• Filed: 02/09/2001
• Issued: 01/27/2009
• Est. Priority Date: 02/09/2000
• Status: Expired due to Fees

• Current Assignee: Pharma Mar, S.A.
• Original Assignee: Pharma Mar, S.A.
• Inventors: Giralt, Ernest, Lopez, Angel, Royo, Miriam, Jimenez, Jose Carlos, Rodrigues, Ignacio, Albericio, Fernando, Manzanares, Ignacio
• Primary Examiner(s): Tsang; Cecilia
• Assistant Examiner(s): Harle; Jennifer I
• Application Number:
  US10/182,881
• Publication Number:
  US 20040214755A1
• Time in Patent Office: 2,909 Days
• Field of Search: 530/350
• US Class Current: 530/327
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68

Abstract

A process is provided for preparing kahalalide F and which leads to other kahalalide mimic compounds having useful biological activity.

Claims

1. A compound selected from the group consisting of:

5-MeHex-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-Val-Phe-Z-Dhb-Val);

5-MeHex-D-Val-Thr-D-Val-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-Val-Phe-Z-Dhb-Val);

5-MeHex-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Etg-Val);

5-MeHex-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-D-Etg-Val);

5-MeHex-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-D-Thr-Val);

5-MeHex-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-D-allo-Thr-Val);

5-MeHex-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-D-Phe-Val);

5-MeHex-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-Dpa-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

But-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

But-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-Val-Phe-Z-Dhb-Val);

3-MeBut-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

3-MeBut-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-Val-Phe-Z-Dhb-Val);

3,3-DiMeBut-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

3,3-DiMeBut-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-Val-Phe-Z-Dhb-Val);

4-MePen-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

4-MePen-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-Val-Phe-Z-Dhb-Val);

Hep-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

Hep-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-Val-Phe-Z-Dhb-Val);

Pal-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

Pal-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-Val-Phe-Z-Dhb-Val);

4-DiMeABut-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

2-Hedo-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

4-AcBut-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

4-HOBut-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

Ac-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

TFA-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

AcButBut-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

Lit-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

TFA-Lit-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

Tico-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

H-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

H-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-Val-Phe-Z-Dhb-Val);

5-MeHex-D-Val-Thr-Val-D-Val-D-Pro-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

5-MeHex-D-Val-Thr-Val-D-Val-D-Pro-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-Val-Phe-Z-Dhb-Val);

5-MeHex-D-Val-Thr-Val-D-Val-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

5-MeHex-D-Val-Thr-Val-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

5-MeHex-D-Val-Thr-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

5-MeHex-D-Val-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val);

5-MeHex-D-allo-Ile-cyclo(D-allo-Thr-D-a/Io-Ile-D-Val-Phe-Z-Dhb-Val);

IBut-D-allo-Ile-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val); and

5-MeHex-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

2. A compound according to claim 1, wherein the compound is 5-MeHex-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-Val-Phe-Z-Dhb-Val).

3. A compound according to claim 1, wherein the compound is 5-MeHex-D-Val-Thr-D-Val-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-Val-Phe-Z-Dhb-Val).

4. A compound according to claim 1, where the compound is 5-MeHex-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Etg-Val).

5. A compound according to claim 1, where the compound is 5-MeHex-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-D-Etg-Val).

6. A compound according to claim 1, wherein the compound is 5-MeHex-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-D-Thr-Val).

7. A compound according to claim 1, wherein the compound is 5-MeHex-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-D-allo-Thr-Val).

8. A compound according to claim 1, wherein the compound is 5-MeHex-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-D-Phe-Val).

9. A compound according to claim 1, wherein the compound is 5-MeHex-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-Dpa-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

10. A compound according to claim 1, wherein the compound is But-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

11. A compound according to claim 1, wherein the compound is But-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-Val-Phe-Z-Dhb-Val).

12. A compound according to claim 1, wherein the compound is 3-MeBut-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

13. A compound according to claim 1, wherein the compound is 3-MeBut-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-Val-Phe-Z-Dhb-Val).

14. A compound according to claim 1, wherein the compound is 3,3-DiMeBut-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

15. A compound according to claim 1, wherein the compound is 3,3-DiMeBut-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-Val-Phe-Z-Dhb-Val).

16. A compound according to claim 1, wherein the compound is 4-MePen-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

17. A compound according to claim 11, wherein the compound is 4-MePen-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-Val-Phe-Z-Dhb-Val).

18. A compound according to claim 1, wherein the compound is Hep-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

19. A compound according to claim 1, wherein the compound is Hep-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-Val-Phe-Z-Dhb-Val).

20. A compound according to claim 1, wherein the compound is Pal-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

21. A compound according to claim 1, wherein the compound is Pal-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-Val-Phe-Z-Dhb-Val).

22. A compound according to claim 1, wherein the compound is 4-DiMeABut-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

23. A compound according to claim 1, wherein the compound is 2-Hedo-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

24. A compound according to claim 1, wherein the compound is 4-AcBut-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

25. A compound according to claim 1, wherein the compound is 4-HOBut-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

26. A compound according to claim 1, wherein the compound is Ac-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

27. A compound according to claim 1, wherein the compound is TFA-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

28. A compound according to claim 1, wherein the compound is AcButBut-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

29. A compound according to claim 11, wherein the compound is Lit-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

30. A compound according to claim 1, wherein the compound is TFA-Lit-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

31. A compound according to claim 1, wherein the compound is Tico-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

32. A compound according to claim 1, wherein the compound is H-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

33. A compound according to claim 1, wherein the compound is H-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-Val-Phe-Z-Dhb-Val).

34. A compound according to claim 1, wherein the compound is 5-MeHex-D-Val-Thr-Val-D-Val-D-Pro-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

35. A compound according to claim 11, wherein the compound is 5-MeHex-D-Val-Thr-Val-D-Val-D-Pro-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-Val-Phe-Z-Dhb-Val).

36. A compound according to claim 11, wherein the compound is 5-MeHex-D-Val-Thr-Val-D-Val-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

37. A compound according to claim 11, wherein the compound is 5-MeHex-D-Val-Thr-Val-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

38. A compound according to claim 1, wherein the compound is 5-MeHex-D-Val-Thr-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

39. A compound according to claim 1, wherein the compound is 5-MeHex-D-Val-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

40. A compound according to claim 1, wherein the compound is 5-MeHex-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

41. A compound according to claim 1, wherein the compound is IBut-D-allo-Ile-D-Val-Thr-Val-D-Val-D-Pro-Orn-D-allo-Ile-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

42. A compound according to claim 1, wherein the compound is 5-MeHex-cyclo(D-allo-Thr-D-allo-Ile-D-Val-Phe-Z-Dhb-Val).

43. A composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or diluent.

44. A method of synthesizing a compound according to claim 1, wherein said compound comprises a cyclic portion, said method comprising a step of forming an amide bond between a carboxylic group of a (D or L) Val moiety and an amino group of a Phe moiety to accomplish a ring closure and form the cyclic portion of the compound according to claim 11, and wherein the starting material and product are optionally protected by one or more protecting groups, and wherein the carboxylic group participating in the amide bond formation and/or the amino group participating in the amide bond formation may optionally be protected or activated.

45. A method of treating cancer comprising administering a therapeutically-effective amount of a compound according to claim 1, wherein said cancer is selected from the group consisting of lung cancer, colon cancer, prostate cancer, lymphoma, and melanoma.

46. A compound having the following Formula II:

47. A composition comprising a compound according to claim 46 and a pharmaceutically acceptable carrier or diluent.

48. A method of synthesizing a compound according to claim 46, comprising a ring closure according to the following scheme:

49. A method of treating cancer comprising administering a therapeutically-effective amount of a compound according to claim 46, wherein said cancer is selected from the group consisting of lung cancer, colon cancer, prostate cancer, lymphoma, and melanoma.